Expression of human amyloid precursor protein in the skeletal muscles of Drosophila results in age- and activity-dependent muscle weakness
© Kim et al; licensee BioMed Central Ltd. 2011
Received: 30 September 2010
Accepted: 25 April 2011
Published: 25 April 2011
One of the hallmarks of Alzheimer's disease, and several other degenerative disorders such as Inclusion Body Myositis, is the abnormal accumulation of amyloid precursor protein (APP) and its proteolytic amyloid peptides. To better understand the pathological consequences of inappropriate APP expression on developing tissues, we generated transgenic flies that express wild-type human APP in the skeletal muscles, and then performed anatomical, electrophysiological, and behavioral analysis of the adults.
We observed that neither muscle development nor animal longevity was compromised in these transgenic animals. However, human APP expressing adults developed age-dependent defects in both climbing and flying. We could advance or retard the onset of symptoms by rearing animals in vials with different surface properties, suggesting that human APP expression-mediated behavioral defects are influenced by muscle activity. Muscles from transgenic animals did not display protein aggregates or structural abnormalities at the light or transmission electron microscopic levels. In agreement with genetic studies performed with developing mammalian myoblasts, we observed that co-expression of the ubiquitin E3 ligase Parkin could ameliorate human APP-induced defects.
These data suggest that: 1) ectopic expression of human APP in fruit flies leads to age- and activity-dependent behavioral defects without overt changes to muscle development or structure; 2) environmental influences can greatly alter the phenotypic consequences of human APP toxicity; and 3) genetic modifiers of APP-induced pathology can be identified and analyzed in this model.
Keywordsamyloid precursor protein (APP) Drosophila muscle mitochondria electron microscopy apoptosis Parkin
Amyloid precursor protein (APP) is a type I glycotransmembrane protein with a large extracellular domain and a short cytoplasmic tail [reviewed in 1]. Its role in normal biological processes is poorly defined, but there is mounting evidence that it plays both autocrine and endocrine roles in neurite growth and enhanced memory function in mice [2, 3].
APP became the subject of intense investigation when it was identified as a risk factor for Alzheimer's disease (AD) . Individuals with an extra copy of the APP gene due to trisomy of chromosome 21 (Down Syndrome) also display early onset AD . One point mutation in APP, referred to as the Swedish mutation, results in an early onset familial AD .
APP can be subjected to combinatorial cleavage by three different intramembrane secretases (α, β, and γ) to create a number of smaller peptides . Cleavage by α-secretase, known as a non-amyloidogenic pathway, is responsible for a default secretory pathway and predominates in all non-neuronal cells. Cleavage by BACE (β-site APP cleaving enzyme) represents a minor pathway in most cell types, except for neurons. Like α-secretase cleavage of APP, the BACE-mediated fragment of APP undergoes further proteolysis by a γ-secretase complex to generate small peptides that typically range between 40-44 amino acids, although 46 amino acid fragments can be found in skeletal muscles. APP cleavage products are enriched in the brains of some AD patients , and exposure to the Aβ42 fragment is highly neurotoxic both in vitro and in in vivo animal models [9, 10].
In addition to its well-documented roles in neurodegeneration, APP and its cleaved products have been also implicated in other diseases, most notably sporadic inclusion body myositis (s-IBM) , the most common skeletal muscle disorder of the elderly [12, 13]. It has been reported that muscle biopsies from individuals with s-IBM contain Congo Red inclusions that are immunopositive for both APP  and Aβ42. However, this is not a universal observation , and proteomic analysis of IBM samples failed to reveal any APP proteolytic products . In fact, a fundamental role for APP in the pathogenesis of s-IBM has been questioned recently [12, 17, 18].
While the role of APP in s-IBM awaits further analysis of clinical samples, it has been demonstrated that ectopic expression of either APP (either wild-type or Swedish mutant) or Aβ42 is sufficient to induce cell death in skeletal muscle either in vitro[19, 20] or in vivo[21–23]. The biology of muscle makes it a much more tractable tissue to study than the central nervous system. Thus, studies designed to examine the effects of APP on muscle development and physiology may provide new insights into the general mechanisms that mediate APP induced pathogenesis.
To help define the mechanisms that could mediate APP toxicity in muscle, and to develop a genetic model for testing genetic and environmental interventions that might reduce APP-induced pathogenesis, we generated transgenic flies that express human APP in the skeletal muscles. We found that both genetic and environmental factors can interact to enhance or reduce APP-induced behavioral defects. These data suggest that the transgenic fly may represent a useful tool for defining the molecular mechanisms that mediate APP-induced muscle pathology and for identifying genetic and chemical modulators.
Results and Discussion
Muscle specific expression of human amyloid precursor protein (hAPP) induces an age-dependent reduction in climbing and flying activity
In order to study the role of human APP (hAPP) on the development and function of skeletal muscles, we took advantage of a transgenic fly line that expresses hAPP under the control of the Upstream Activating Sequence (UAS) . These flies were crossed to a line that expresses the Gal4 transcription factor under the control of the muscle transcription factor Dmef, which expresses in all skeletal muscles and a few circadian neurons within the brain .
To assess the effects of ectopic hAPP on behavior, flies were tested for their ability to climb (Figure 1A). Both nontransgenic (w 1118 ●) and LacZ-expressing (■) flies displayed comparable levels of climbing activity during the one-month testing period. Transgenic flies expressing hAPP exhibited wild-type levels of climbing activity during the first two weeks of adulthood, but it declined during the subsequent weeks (Figure 1C) so that by the end of the fourth week, only about 20% of the transgenic flies could climb. In contrast, 75% of 1-month old wild-type w 1118 control animals could climb. The climbing defect observed in transgenic flies was not due to a loss in their negative-geotropism, but rather, an apparent loss of strength that caused them to fall from the test cylinder before they could reach the test mark.
To evaluate flying behavior, animals were dropped into an oil-coated 500 ml graduated cylinder and then scored for their ability to remain near the top. Approximately 55% of the hAPP-expressing flies (dark gray) fell to the bottom 200 ml of the cylinder (poor fliers), while only about 12% of the controls (light gray) fell that distance (Figure 1D). Conversely, about 70% of the controls (light gray) remained within the top 200 ml (normal fliers), while only 20% of the transgenic flies (dark gray) were in this category. Taken together, the climbing and flying assays suggest that ectopic expression of hAPP results in an age-dependent defect in motor ability.
Electrophysiological analysis of the neuromuscular junction
Amplitude sizes of recordings from the DLFM and the TTM
1 week w 1118
2 week w 1118
1 week Dmef/ hAPP
3 week Dmef/ hAPP
Anatomical analysis of muscles
Environmental control of muscle pathogenesis in hAPP-expressing flies
One possible mechanism for the differential effects of the vial composition on the development of muscle weakness is that the smoothness of glass relative to plastic requires more muscle strength to climb. To test this hypothesis, we siliconized plastic vials to make their surfaces smoother, and then tested new groups of control and transgenic animals. Survival was comparable in all three types of vials (data not shown). Wild type control flies climbed equally well in all three types of vials until week 3. After that, there was a small but statistically significant decline in climbing ability for flies reared in glass vials (▲) relative to coated (■) and uncoated plastic vials (●) (Figure 5C). However, the effects of vial type were much more dramatic in the hAPP transgenic flies (Figure 5D). Transgenic flies reared in siliconized plastic vials (■) displayed a rapid loss of climbing activity beginning even after the first week relative to those reared in glass (▲) or uncoated plastic vials (●). Between three and four weeks, there was a dramatic decline in climbing for hAPP transgenic flies reared in glass vials. These data suggest that the environmental factors (vial material) can have a significant impact on APP-induced pathogenesis.
Coexpression of human Parkin rescues a hAPP-mediated climbing defect
APP has been the focus of intensive investigation for its possible role in human diseases, most notably Alzheimer's disease. Numerous studies have demonstrated that ectopic expression of APP, or its proteolytic products, most notably Aβ42, can trigger synapse loss and neuron death in both in vitro and in vivo models [9, 10]. In fly, ectopic expression of Aβ42 or Aβ40 results in age-dependent neuron loss . Interestingly, males were more severely impacted than females, although this may reflect differences in driver expression rather than differential gender sensitivity.
These same proteins have been proposed to accumulate within aggregates in patients with other diseases as well, such as inclusion body myositis , although this observation has been controversial [17, 18]. Nevertheless, experimental studies have demonstrated that ectopic expression of either APP or Aβ42 is sufficient to induce muscle cell death both in vitro[19, 20] and in transgenic mouse models [22, 23, 31]. In the nematode Caenorhabditis elegans, expression of Aβ42 results in protein aggregations within body wall muscles that result in paralysis and reduced longevity [32–34].
The transgenic fly model described in the present study complements and extends some of the data obtained with mouse and worm models, as well as some of the features of s-IBM. In s-IBM patients and animal models designed to simulate the disorder, individuals produce muscles that appear to be morphologically and physiologically normal, but develop progressive age-dependent muscle weakness in mid-to-late adulthood [12, 22, 32] (Figure 1C and 1D). This loss of muscle strength is not accompanied by detectable changes in neuromuscular synapse activity, suggesting that the defects arise within the muscles themselves. Indeed, we did not observe any changes in following frequency or spike amplitude in the muscles of our hAPP-expressing animals (Figure 2). These data would argue against a negative influence of hAPP expression in the small subset of circadian neurons in the brain that also express MEF2 
The fly model described in this study does differ from both s-IBM and other hAPP transgenic mouse and worm models in that they did not produce protein aggregates within the sarcoplasm that can be detected with either Congo Red staining (data not shown) or ultrastructural analysis (Figure 4). It is possible that the level of hAPP expression was below the threshold required for macro-aggregation, or alternatively, that flies have intracellular mechanisms that limit aggregate formation. It has been noted that flies do not make inclusion bodies in the skeletal muscles with other aggregation prone proteins, like the polyglutamine-rich Huntington protein . Nevertheless, the present fly model may provide insight into the molecular mechanisms that mediate hAPP induced pathology.
Several mechanisms have been proposed for the toxic effects of APP on skeletal muscle function including: defective regulation of ryanodine receptor-dependent sarcoplasmic Ca2+ release , CD8+ cytotoxic T cell invasion , an autophagic mechanism , and myostatin activity .
The observation that ectopic expression of the ubiquitin E3 ligase Parkin can rescue the hAPP-associated defects in climbing in our transgenic model agrees well with in vitro results from other groups [16, 27, 40, 41]. At least two possible Parkin associated mechanisms can ameliorate ectopic APP-induced behavioral defects. In mammalian muscle, Parkin prevents hAPP-induced muscle degeneration by inhibiting accumulation of toxic Aβs and also protects cells from mitochondrial-specific toxins like rotenone and carbonyl cyanide 3-chlorophenylhydrazone, but not from other toxins like calcium ionophore A23187 or H2O2. Loss of function mutations in the parkin gene result in age-dependent defects in flight muscle maintenance in fly and are also associated with mitochondrial defects . Interestingly, these defects can be prevented by increased mitochondrial fission . Taken together, these data support the hypothesis that Parkin may reduce mitochondrial oxidative stress or maintain respiratory functions to help preserve mitochondrial integrity.
We have demonstrated that environmental factors, such as rearing surface (glass versus plastic), have a dramatic effect on the timing and severity of hAPP-induced pathogenesis, suggesting a possible interplay between environmental and genetic factors. To our knowledge, this is the first report of any behavioral activities that can be tied to the material used for rearing flies. The simple manipulation of changing the rearing vessel may represent a valuable tool for genetic screens in fly designed to identify work-associated genes in fly muscle.
Only limited data exist on the role of exercise in the progression of myopathies in human [44, 45]. Interestingly, Arnardottir et al. have suggested that moderate exercise may retard the symptoms of s-IBM. Rearing flies in plastic vials greatly reduced the timing and severity of symptoms relative to rearing in glass (Figure 5A). Since the only difference between animals reared in glass versus plastic was the nature of the vessel, we speculated that surface properties accounted for the observed effects. Glass vials have a smoother surface than plastic and therefore it is presumably harder for the fly to climb. This extra work would increase the mechanical stress on the muscle fibers and might contribute to damage or generation of reactive oxygen species (ROS) by mitochondria. We tried to test this hypothesis directly by setting up devices that would force the animal to walk more, such as placing the vials on a slowly moving rocking table. Unfortunately, these efforts to voluntarily increase motor activity did not appear to alter animal behavior, so instead we changed the surface properties of the plastic vials by siliconizing them. This subtle manipulation had a profound effect on the time course and severity of the hAPP-induced abnormal activities. This effect was specific to the muscles that were forced to work, since this treatment did not alter flying behavior.
In this study, we generate a transgenic Drosophila model that targets the expression of hAPP to the skeletal muscles in order to understand its effect on muscle development and degeneration in the adult. Ectopic expression of hAPP causes age- and activity-dependent muscle weakness without concomitant structural damage that can be discerned at either the light or electron microscopic levels. The effects of ectopic hAPP can be ameliorated by hParkin expression. Taken together, these data suggest that in Drosophila, hAPP-induced muscle deficits are mediated by not only genetic, but also environmental factors, and that muscle work/stress may contribute to pathogenesis. This animal model is useful to identify additional genetic and environmental modulators and understand underlying mechanisms.
Generation of transgenic UAS-human Parkin Drosophila lines
In order to generate UAS-human Parkin, pRK5-myc-Parkin generously provided by Dr. Dawson  and a pUAST vector were digested with EcoR I and Not I restriction enzymes (Promega) and ligated at 16°C overnight with T4 ligase (Promega). The construct, pUAST-myc-human Parkin was sent to the Transgenic Drosophila Fly Core (Charlestown, MA) for embryonic injections. Transgenic lines were selected and cultured at room temperature.
Transgenic flies expressing human APP under the control of the Gal4 upstream activating sequence (UAS) were provided by Dr. Kalpana White . A Dmef-GAL4 line driving the expression Gal4 in mesodermal precursors  was provided by Dr. Leo Pallanck. Progenies from these crosses were maintained at 25°C with 12 hour-light/dark cycle. Both males and females were used in each experiment.
Climbing Assay and flight assay
Flies were divided into 5-7 groups of 25 flies each and reared in standard glass or plastic vials (Genesee Scientific) as noted. In some experiments plastic vials were siliconized with glass cleaner (Rain-X). The vials were exchanged every two to three days and animals were scored weekly in the climbing assay. Briefly, after a 1 minute acclimation, the percentage of flies that could climb past the 30ml mark in a 50ml cylinder within 30 seconds was scored as successful. Trials were performed 3 times/vial. After five weeks, the flies were subjected to the flying test. The animals were dropped into a 500ml graduate cylinder coated with mineral oil. The number of immobilized flies was determined for each 100 ml section of the cylinder.
Statistical significance was determined using Student's T test and one-way-analysis of variances (ANOVA) using GraphPad Prism software (GraphPad Software, La Jolla, CA). Data were considered statistically significant when their p values were 0.05 or less.
Standard methods were used to get intracellular recordings from the dorsal longitudinal flight muscle (DLFM) and the tergotrochanteral muscle (TTM) . Flies were anesthetized and waxed, ventral side down, onto a small podium in a Petri dish. The motorneurons were either indirectly stimulated via the Giant Fiber (GF) in the brain or directly with thoracic stimulation using two etched tungsten electrodes and by providing pulses of 40-60V for 0.03ms using a Grass S44 stimulator (Grass Instruments). A tungsten electrode placed in the abdominal cavity served as a ground. Glass electrodes pulled to a resistance of 40-60MW were filled with saline and were driven through the cuticle into the DLFM and TTM muscle fibers. Signals were amplified, digitized and analyzed with pClamp 10 software to monitor amplitude size and the ability of the muscle membrane to follow multiple stimuli at 100HZ (Getting Instruments and Molecular Devices).
Flies were collected at different ages, the heads and abdomens removed, and the carcass immersed in 4% paraformaldehyde overnight at 4°C. They were then dehydrated, embedded in paraffin and sectioned at 10 μm followed by staining with hematoxylin and eosin for light microscopy. For transmission electron microscopy, flies were prepared as previously described [48, 49]. A fly was placed thorax facing upward and fully covered in a droplet of Optimal Cutting Temperature (OCT) compound on a glass microscope slide. The fly was snap frozen in liquid nitrogen (-196°C) and then gently fractured with a liquid nitrogen-chilled razor blade struck with a hammer to longitudinally bisect the flies. Care was taken to ensure that the droplet of tissue was completely submerged in liquid nitrogen throughout the fracturing process, so that at no time was any sample exposed to air and that the razor blade contacted the OCT compound, not the thorax itself. The split pieces were immediately transferred to a container of primary fixative made of 2.5% glutaraldehyde in 0.1 M phosphate buffer at pH 7.4, and allowed to thaw and fix overnight at 4°C. The fixative was changed several times to ensure its concentration was not altered by the thawing OCT. After rinsing in 0.1 M NaPO4 buffer at pH 7.4, the tissue was post-fixed in 2% osmium tetroxide in 0.1 M NaPO4 buffer at pH 7.4 for one hour. The sample was then rinsed in distilled water and stained with 1% uranyl acetate for 30 minutes. It was then rinsed in water and dehydrated through an ethanol series from 30% to 100%. The sample was then infiltrated with Spurr's extra low viscosity resin, and after embedding, mounted fracture-surface up and thin-sectioned with a diamond knife for TEM analysis. Multiple sections from at least eight different flies of each genotype and age were examined for each experiment.
- hAPP :
human amyloid precursor protein
- AD :
- s-IBM :
sporadic inclusion body myositis
- A ß:
ß amyloid peptide
- UAS :
upstream activating sequence
- LacZ :
- Dmef :
Drosophila myocyte enhancer factor
- GF :
- DLFM :
dorsal longitudinal flight muscle
- TTMn :
- TTM :
- SR :
- ROS :
reactive oxygen species
We thank Dr. by Dr. Kalpana White for the UAS-hAPP transgenic flies and Dr. Leo Pallanck for the Dmef-GAL4 line. This project was supported by NIH grant R01NS042898 to LMS. MR, SS., and CTW were supported by Howard Hughes Medical Institute Grant 52006307 to Mount Holyoke College and TAG was supported by a grant R01HD050725 from the NIH. We thank Ms. Christine Brown for technical and editorial assistance.
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